Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine/threonine kinase. HPK1 kinase activity can be induced by activation signals generated by various different cell surface receptors found in hematopoietic cells upon ligand engagement. Ligand engagement or antibody-mediated crosslinking of T cell receptors (TCR), B cell antigen receptor (BCR) (Liou et al., 2000, Immunity 12:399), transforming growth factor β receptor (TGF-βR) (Wang et al., 1997. J. Biol. Chem. 272:22771; Zhou et al., 1999, J. Biol. Chem. 274:13133), erythropoietin receptor (EPOR) (Nagata et al., 1999, Blood 93:3347), and Fas (Chen et al., 1999, Oncogene 18:7370) can induce HPK1 kinase activity. Each receptor utilizes unique, but sometimes overlapping, signaling mechanisms to activate HPK1. HPK1 acts as a down-modulator of T and B cell functions through the AP-1, NFKB, Erk2, and Fos pathways; for example, HPK1 has been implicated as a negative regulator of signal transduction in T-cells through phosphorylation and activation of the T-cell receptor adaptor protein SLP-76 (Di Bartolo et al., 2007, Exp. Med. 204:681), which leads to subsequent downregulation of the AP-1 and Erk2 pathways. In B-cells, HPK1 downregulates B-cell receptor (BCR) signaling through phosphorylation of the SLP-76 paralog BLINK (Wang et al., 2012, J. Biol. Chem. 287:11037).
Thus, HPK1 is now viewed as a possible target for therapeutic intervention. For example, it has been reported that HPK1 can be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 December; 54(1-3):262-5). Specifically, targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1 (−/−) T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1 (−/−) T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1 (−/−) DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine.
When evaluating if a small-molecule inhibitor of HPK1 would capture the phenotype of mice with targeted disruption of the gene, it is important to consider the non-catalytic roles of the protein. In particular, while full-length HPK1 can promote TCR-mediated activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, the catalytically inactive cleavage product HPK1-C can suppress NF-κB activation upon TCR restimulation, leading to activation-induced cell death (AICD) (Brenner et al., EMBO J. 2005, 24:4279). Taking together the catalytic and non-catalytic roles of HPK1, it is possible that blocking the HPK1 kinase activity with a small-molecule inhibitor may promote activation of B- and T-cells, leading to superior anti-tumor immunity, while also facilitating AICD, helping to maintain peripheral immune tolerance. The exact effects of an HPK1 inhibitor would be borne out by testing in mouse models of cancer, such as syngeneic tumor xenografts. Given that HPK1 is not expressed in any major organs, outside the hematopoietic system, it is less likely that an inhibitor of HPK1 kinase activity would cause any serious side effects.
In view of the above, there is a need in the art for novel compounds that can inhibit HPK1.